EP3052482A1 - Novel substituted n, n-dimethylaminoalkyl ethers of isoflavanone oximes as h1-receptor antagonists - Google Patents

Novel substituted n, n-dimethylaminoalkyl ethers of isoflavanone oximes as h1-receptor antagonists

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Publication number
EP3052482A1
EP3052482A1 EP13789395.4A EP13789395A EP3052482A1 EP 3052482 A1 EP3052482 A1 EP 3052482A1 EP 13789395 A EP13789395 A EP 13789395A EP 3052482 A1 EP3052482 A1 EP 3052482A1
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European Patent Office
Prior art keywords
hydrogen
compound
chlorine
fluorine
phenyl
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EP13789395.4A
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German (de)
French (fr)
Inventor
Piotr KOPCZACKI
Mieczyslaw WOSKO
Jaroslaw Walczak
Krzysztof WALCZYNSKI
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Polfarmex SA
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Polfarmex SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel substituted N, N-dimethylaminoalkyl ethers of isoflavanone oximes as Hi-receptor antagonists having valuable pharmacological properties, especially against inflammatory diseases and allergic conditions.
  • Compounds of this invention are antagonists of the histamine- Hi receptors.
  • R is phenyl or substituted phenyl
  • the major structural differences between the compounds of the present invention and those of the said patents and paper is the presence of various substituents at postion 3 of N, N-dimethylaminoalkyl ethers of isoflavanone oximes.
  • the compounds disclosed in this invention present an almost exclusive Hi antihistaminic pharmacological activity and are therefore devoid of action on other pharmacological receptors. Because of this selectivity in action, they are valuable instruments in treating allergic-type conditions.
  • Hi receptor antagonists have proved to be effective therapeutic agents for the treatment of allergic rhinitis.
  • classical antihistamines agents first-generation class
  • CNS central nervous system
  • H x -Antagonists promethazine, diphenhydramine, cyclazine
  • muscarine receptor antagonist activity which may produce anticholinergic side effects.
  • the sedative activity of Hi-antagonists is associated with binding to cerebral Hi receptors.
  • the present invention relates to a compound, including enantiomers, stereoisomers, cis-, trans-isomers and their racemic mixture and mixture of geometric isomers, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general stru
  • Rx and R 2 are, independently, hydrogen, halogen, C 1-3 alkyl or Ci- 3 alkoxy;
  • R 3 is phenyl optionally substituted by R and R 5 which are, independently hydrogen, halogen, Ci -3 alkyl, C x - 3alkoxy, fluoro- , difluoro- and trifluoromethyl, nitrile group, N, N-diC 1-3 alkylamide, carboCi -3 alkoxy or Ci- 3alkylsulphone groups; R 3 is pyridynyl group containing
  • n is one of the integers 1 or 2.
  • a pharmaceutical composition having histamine ⁇ - antagonists activity comprising a histamine blocking 115 effective amount of a compound according to formula (I) mentioned above and a pharmaceutically acceptable carrier .
  • the present invention relates to a group of new compounds with ⁇ , ⁇ -dimethylaminoalkyl ethers of isoflavanone oximes structures having potent selectivity 3 ⁇ 4 antihistaminic activity.
  • Ri and R 2 are, independently, hydrogen, halogen, Ci- 3 alkyl or Ci -3 alkoxy;
  • R 3 is phenyl optionally substituted by R 4 and R 5 which are, independently hydrogen, halogen, Ci_ 3 alkyl, Ci- 3alkoxy, fluoro- , difluoro- and trifluoromethyl, nitrile group, N, N-diC 1-3 alkyl- amide, carboC 1-3 alkoxy or Ci- 3alkylsulphone groups; R 3 is pyridynyl group containing
  • n is one of the integers 1 or 2;
  • the halogen substituent is chlorine, bromine or fluorine.
  • the pharmaceutically acceptable salts are derived from such 140 organic and inorganic acids as: acetic, maleic, malonic, fumaric, lactic, citric, tartaric, succinic, oxalic, hydrochloric, hydrobromic, sulfuric, phosphoric, and similarly known acceptable acids.
  • R x and R 2 can be hydrogen, Ci -3 alkyl, particularly methyl, or halogen, particularly chlorine. 155
  • R x and R 2 are hydrogen.
  • n 1
  • R 4 is hydrogen and R 5 is halogen.
  • R 3 is optionally substituted phenyl preferably the phenyl moiety contains a maximum of one substituent.
  • phenyl groups for R 3 are: phenyl, 3- fluorophenyl, 4 - fluoropheny1 , 3- chlorophenyl , 4-chlorophenyl, 3-bromophenyl, 4- bromophenyl, 3-methoxyphenyl, 4-methoksyphenyl , 4- trifluorometyhylphenyl , 4-nitrilophenyl, 4-
  • acetamidophenyl 4-methylsulfonylphenyl, and 4- carbomethoxyphenyl .
  • R 3 is unsubstituted pyridynyl preferably the pyridynyl moiety contains nitrogen in 3 -position in benzene ring .
  • the compounds of formula (I) exhibit optical and geometrical activity and all isomers in resolved and cis- trans and racemic forms are included within the scope of this invention.
  • the compounds of formula (I) can be prepared by reacting a compound of formula (II)
  • Ri, R 2 and R 3 are as defined with reference to formula (I) with a compound of formula (III)
  • n is one of the integers 1 or 2
  • This reaction can be carried out in a solvent at an elevated temperature, for example at from 40 °C to 80 °C.
  • the choice of solvent is affected by solubility characteristics of the reactants.
  • the solvent is pyridine, a picoline or mixture of picolines or mixture of pyridine or picolines with and Ci -6 alkanol , preferably ethanol or 1-propanol.
  • the pharmaceutically acceptable salts of compounds of 190 formula (I) can be prepared by standard methods, for example by reacting a solution of the compound of formula (I) with a solution of the acid.
  • pyridynyl group containing nitrogen at position 3 or 4 in the benzene ring can be prepared by a three- step synthesis including: palladium-catalyzed cross-coupling reaction of 3-halogenochromones ( IV) with the appropriate arylboronic acids (V) , to isoflavones, reduction with
  • X can be chlorine, bromine or iodine
  • Ri and R 2 are, independently, halogen, Ci -3 alkyl or Ci -3 alkoxy and R 3 is phenyl or substituted phenyl or disubstitutedphenyl or
  • 215 pyridyl group containing nitrogen at position 2 in the benzene ring can be obtained by a two-step synthesis including: cyclxzation reaction of 1- (2-hydroxy- or 4- or 5-substituted or 4 , 5-disubstitutedphenyl) -2-pyridin- or 3- or 4- or 3,4 disubstitutedphenyl-2 -yl-ethanone (VI )
  • a pharmaceutical composition having histamine ⁇ - antagonists activity comprising a histamine blocking effective amount of a compounds of formula (I) .
  • Hi-antagonists by subjecting them to the following standard test procedures for Hi-blocking activity:
  • the pA 2 -values were calculated according to O. Arunlakshana, H.O. Schild, Br. J. Pharmacol. 1959, 14, 48-58. The pA values were compared with the potency of pyrilamine.
  • the potency of an antagonist is expressed by its pA 2 value, calculated from the Schild regression analysis where at least three concentrations were used.
  • the pA 2 values were compared with the potency of thioperamide .
  • Hi- receptor antagonists 425 useful in the treatment of mammals experiencing conditions such as asthma, hay fever, allergic rhinitis, atopic dermatitis, conjunctivitis, pruritis, and eczema, or other responses where histamine is released and acts on Hi receptors.
  • they may be administered 430 topically or systemically.
  • Topical administration is advantageously achieved with creams, ointments or lotion, or via aerosol introduction into the respiratory tract.
  • Systematic administration may be orally, nasally, intrabronchially, parenterally or rectally. In each 435 instance, conventional formulation amenable to use in desired administration route is appropriate.
  • tablets and capsules may be prepared for oral administration, suppositories for rectal administration, isotonic aqueous solutions for intravenous, subcutaneous 440 of intramuscular injection and in aerosol suspensions for inhalation.
  • the appropriate dosage is determined on a subjective basis for initial administration in small amounts, c.a. 0.5 -
  • the dosage is personalized in this manner for each patient, based upon size, age, type of discomfort, degree of

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to compounds of formula (I), and salts thereof and the pharmaceutical composition containing them in treatment of various diseases, as allergic rhinitis where R1 and R2 are, independently, hydrogen, halogen, C1_3 alkyl or C1-3alkoxy; R3 is phenyl optionally substituted by R4 and R5 which are, independently hydrogen, halogen, C1-3 alkyl, C1-3-alkoxy, fluoro-, difluoro- and trifluoromethyl, nitrile group, N,N-diC1-3alkyl- amide, carboC1-3 alkoxy or C1-3alkylsulphone groups; R3 is pyridyl group containing nitrogen at various positions in the benzene ring, n is one of the integers 1 or 2.

Description

Novel substituted N, N-dimethylaminoalkyl ethers of isoflavanone oximes as Ηχ-receptor antagonists
TECHNICAL FIELD
The present invention relates to novel substituted N, N-dimethylaminoalkyl ethers of isoflavanone oximes as Hi-receptor antagonists having valuable pharmacological properties, especially against inflammatory diseases and allergic conditions. Compounds of this invention are antagonists of the histamine- Hi receptors.
BACKGROUND ART
Tsujikawa et al . , in JP pat. No. 45027577 granted Sep. 9 1970 discloses histamine Ηχ-receptor antagonists which also possess anti-acetlocholine activities of the formula:
R is phenyl or substituted phenyl; and
Rx=R2 is methyl
Krolikowska and Perka - Acta Polon. Pharm, XXXIV, No. 4, 445-446, 1977 and Jerzmanowska and Blasinski PL Pat. No. 100895 granted February 15 1979; - is quite similar to disclosure of Tsujikawa et al . , although R may also be methyl or disubstituted phenyl and Ri=R2 is ethyl. These compounds are weak antihistaminic agents with spasmolytic properties.
The major structural differences between the compounds of the present invention and those of the said patents and paper is the presence of various substituents at postion 3 of N, N-dimethylaminoalkyl ethers of isoflavanone oximes. The compounds disclosed in this invention present an almost exclusive Hi antihistaminic pharmacological activity and are therefore devoid of action on other pharmacological receptors. Because of this selectivity in action, they are valuable instruments in treating allergic-type conditions.
DISCLOSURE OF INVENTION
Technical problem
Histamine plays a key role in allergy and inflammation. The Hi receptor has been a target for drug discovery for many years, and Hi receptor antagonists have proved to be effective therapeutic agents for the treatment of allergic rhinitis. However, classical antihistamines agents (first-generation class) have several limitations which complicate their clinical use, such as nonselective pharmacological activity and central nervous system (CNS) activity. Hx-Antagonists (promethazine, diphenhydramine, cyclazine) demonstrate e.g. muscarine receptor antagonist activity, which may produce anticholinergic side effects. The sedative activity of Hi-antagonists is associated with binding to cerebral Hi receptors. The focus of newer Ηχ -antagonists has been an efficacy with diminished sedative liability. These agents (second-generation class - "nonsedating antihistamines") are used in rhinitis, hay fever, asthma and obstructive airway disease. As opposed to classical antihistamine, the more recent Ηχ-antagonists loratadine, astemizole, and temelastine, have poor access to C S which produces nonsedating antihistaminic activity in the clinic. However since late 1980's, reports began to appear indicating that patients who took intentional overdoses of terfenadine or astemizole could develop a classical form of ventricular arrhythmia, torsades de pointes, which has been previously associated with quinidine and other antiarrhythmic drugs. Many Ηχ - antihistamines have now been examined for their cardiac actions. Astemizole and terfenadine, among the others, belong to group of antihistamines with cardiac effects at their antihistamine concentrations, and from this reason were removed from the market. The newest antihistamine agent, desloratadine, an active metabolite of loratadine has been categorized under the third-generation antihistamine . Technical Solution
The present invention relates to a compound, including enantiomers, stereoisomers, cis-, trans-isomers and their racemic mixture and mixture of geometric isomers, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general stru
wherein
Rx and R2 are, independently, hydrogen, halogen, C1-3alkyl or Ci-3alkoxy;
85 R3 is phenyl optionally substituted by R and R5 which are, independently hydrogen, halogen, Ci-3alkyl, Cx- 3alkoxy, fluoro- , difluoro- and trifluoromethyl, nitrile group, N, N-diC1-3alkylamide, carboCi-3alkoxy or Ci- 3alkylsulphone groups; R3 is pyridynyl group containing
90 nitrogen at various positions in the benzene ring,
n is one of the integers 1 or 2.
The compound of formula (I) mentioned above where Ri and R2 are Ci_3alkyl groups, and R3 = phenyl, and the optional substituents in R4 and R5 are hydrogen, fluorine, 95 chlorine or bromine .
The compound of formula I mentioned above where Ri and R2 are Ci-3alkoxy groups and R3 = phenyl, and the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine .
100 The compound of formula (I) where Rx and R2 are fluorine, chlorine or bromine groups and R3 = phenyl, and the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine.
The compound of formula (I) where Ri and R2 are hydrogen 105 and R3 = phenyl, and the optional substituents in R4 are hydrogen or methyl or chlorine and R5 are hydrogen or methyl or fluorine or chlorine or methyl group or methoxy group or nitrile group.
The compound of formula (I) where Ri and R2 are hydrogen, 110 fluorine, chlorine or bromine and R3 = unsubstituted pyridynyl, the pyridynyl moiety contains nitrogen at 3 - position in benzene ring.
A pharmaceutical composition having histamine Ηχ- antagonists activity comprising a histamine blocking 115 effective amount of a compound according to formula (I) mentioned above and a pharmaceutically acceptable carrier .
The present invention relates to a group of new compounds with Ν,Ν-dimethylaminoalkyl ethers of isoflavanone oximes structures having potent selectivity ¾ antihistaminic activity.
The compounds subject of the present invention have the following general formula (I) :
pharmaceutically acceptable acid addition salts
therefore, in which
Ri and R2 are, independently, hydrogen, halogen, Ci-3alkyl or Ci-3alkoxy;
130 R3 is phenyl optionally substituted by R4 and R5 which are, independently hydrogen, halogen, Ci_3alkyl, Ci- 3alkoxy, fluoro- , difluoro- and trifluoromethyl, nitrile group, N, N-diC1-3alkyl- amide, carboC1-3alkoxy or Ci- 3alkylsulphone groups; R3 is pyridynyl group containing
135 nitrogen at various positions in the benzene ring,
n is one of the integers 1 or 2;
In the compounds involved in this invention, the halogen substituent is chlorine, bromine or fluorine. The pharmaceutically acceptable salts are derived from such 140 organic and inorganic acids as: acetic, maleic, malonic, fumaric, lactic, citric, tartaric, succinic, oxalic, hydrochloric, hydrobromic, sulfuric, phosphoric, and similarly known acceptable acids.
Examples of alkyl groups for R3. and R2 / for R3 = phenyl, 145 and the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine.
Examples of alkoxy groups for Ri and R2 , for R3 = phenyl, and the optional substituents in R and R5 are hydrogen, fluorine, chlorine or bromine.
150 Examples of halogens for Ri and R2 , for R3 = phenyl, and the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine..
Where R3 is phenyl, Rx and R2 can be hydrogen, Ci-3alkyl, particularly methyl, or halogen, particularly chlorine. 155 Preferably Rx and R2 are hydrogen.
Preferably n is 1.
Preferably R4 is hydrogen and R5 is halogen.
When R3 is optionally substituted phenyl preferably the phenyl moiety contains a maximum of one substituent.
160 Examples of optionally substituted phenyl groups for R3 are: phenyl, 3- fluorophenyl, 4 - fluoropheny1 , 3- chlorophenyl , 4-chlorophenyl, 3-bromophenyl, 4- bromophenyl, 3-methoxyphenyl, 4-methoksyphenyl , 4- trifluorometyhylphenyl , 4-nitrilophenyl, 4-
165 acetamidophenyl , 4-methylsulfonylphenyl, and 4- carbomethoxyphenyl . When R3 is unsubstituted pyridynyl preferably the pyridynyl moiety contains nitrogen in 3 -position in benzene ring .
The compounds of formula (I) exhibit optical and geometrical activity and all isomers in resolved and cis- trans and racemic forms are included within the scope of this invention.
The compounds of formula (I) can be prepared by reacting a compound of formula (II)
where
Ri, R2 and R3 are as defined with reference to formula (I) with a compound of formula (III)
n is one of the integers 1 or 2
This reaction can be carried out in a solvent at an elevated temperature, for example at from 40 °C to 80 °C. The choice of solvent is affected by solubility characteristics of the reactants. Preferably the solvent is pyridine, a picoline or mixture of picolines or mixture of pyridine or picolines with and Ci-6alkanol , preferably ethanol or 1-propanol. The pharmaceutically acceptable salts of compounds of 190 formula (I) can be prepared by standard methods, for example by reacting a solution of the compound of formula (I) with a solution of the acid.
The compound of formula ( II ) in which Ri=R2=H , and R3 is phenyl or substituted phenyl or disubstitutedphenyl or
195 pyridynyl group containing nitrogen at position 3 or 4 in the benzene ring can be prepared by a three- step synthesis including: palladium-catalyzed cross-coupling reaction of 3-halogenochromones ( IV) with the appropriate arylboronic acids (V) , to isoflavones, reduction with
200 NaBH4 in alcohol to isoflavan-4 -ols and oxydation of hydroxyl group with pyridinium chlorochromate (PCC) to desired isoflavanones ( II ) (Hoshino et al . Bulletin of the Chemical Society of Japan, 1988 , vol. 61, p. 3008 - 3010) . Pyridynyl derivatives of isoflavanones
205 ( II ) can be directly obtained by hydrogenation of isoflavone with a catalytic amount of palladium on etone (Delcanale et al . , EP 1229036 (2002))
Where X can be chlorine, bromine or iodine
with a compound of formula (V)
The compound of formula ( II ) in which Ri and R2 are, independently, halogen, Ci-3alkyl or Ci-3alkoxy and R3 is phenyl or substituted phenyl or disubstitutedphenyl or
215 pyridyl group containing nitrogen at position 2 in the benzene ring can be obtained by a two-step synthesis including: cyclxzation reaction of 1- (2-hydroxy- or 4- or 5-substituted or 4 , 5-disubstitutedphenyl) -2-pyridin- or 3- or 4- or 3,4 disubstitutedphenyl-2 -yl-ethanone (VI )
220 with N, N-dimethylformamide dimethyl acetal (VII ) , to 3- substituted-4H-chromen-4-ones and hydrogenation with a catalytic amount of palladium on charcoal in acetone yield to desired isoflavanones (Lowe at al, Journal of Heterocyclic Chemistry, 2004, 41(3), 317-326; Oldfield at
225 al. Tetrahedron, 2004, 60(8), 1887-1893).
where
with a compound of formula (VI ) The compounds of formula (III) were obtained by standard methods according to Cerri et al . J". Med. Che . , 2000, 43 (12) , pp 2332-2349.
A pharmaceutical composition having histamine Ηχ- antagonists activity comprising a histamine blocking effective amount of a compounds of formula (I) .
The following examples illustrate the preparation of representative compounds of this invention.
EXAMPLE 1
Preparation of N,N-dimethyl-2- [ [3- (4-methylphenyl) -2, 3- dihydrochromen-4-ylidene] - amino] oxyethanamine
To a solution of 4 ' -methylisoflavone (0.365 g, 0.00155 mole) in methanol (36.5 mL) , sodium borohydride was added in portions over 15 minutes at room temperature . The reaction mixture was stirred for a further 15 minutes and 120 mL water was added. This was extracted with ethyl acetate . The organic layer was dried over anhydrous magnesium sulphate and concentrated to yield 0.37 g of crude 4 ' -methylisoflavan- -ol which was used without purification in the next step.
To a solution of the above product (0.37 g) in dichloromethane (9.2 mL) , pyridinium chlorochromate (PCC) (0.67 g, 0.0031 mole) and anhydrous sodium acetate (0.141 g, 0.00172 mole) were added. The reaction mixture was
255 stirred at room temperature for lh and 250 mL water was added. This was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulphate and concentrated to give the crude 4 ' -methylisoflavanone which was purified by column chromatography.
260 Ci6H1402, (238.29); yield 81%; mp 86.5-87.0°C, XK NMR
(CDCI3 , 300 MHz , ppm) : δ 7.95 (d, J=7.8 Hz, 1H, 5-H) , 7.49 (t, J=7.8 Hz, 1H, 7-H), 7.15 (m, 4H, Ar-H) , 6.99- 7.06 (m, 2H, 6-H, 8-H) , 4.63 (d, J=6.6 Hz, 2H, 2-H) , 3.96 (t, .7=6.9 Hz, 1H, 3-H) , 2.33 (s, 3H, Ar-CH3) ; TLC
265 (hexane : ethyl acetate - 9 : 1) , Rf 0.68
To a solution of 4 ' -methylisoflavanone (0.289 g, 0.0012 mole) in mixture of pyridine (6.12 mL) and dry ethanol (2.45 mL) , 2- (dimethylamino) ethoxyamine dihydrochloride (0.433 g, 0.00245 mole) was added. The reaction mixture
270 was stirred at 80 °C for 15 h while being monitored by
TLC. After completion, the reaction mixture was poured into water (50 mL) and extracted with ether. The ethereal solution was dried over anhydrous magnesium sulphate. The solvent was evaporated to give the crude , N-dimethy1- 2 -
275 [ [3- (4-methylphenyl) -2, 3 -dihydrochromen-4 - ylidene] amino] oxyethan- amine as a sticky oil which was purified by column chromatography.
C20H24 2O2 (324.43); yield 88%; XH NMR (CDC13, 300 MHz, ppm): δ 7.98 (dd, 1H, J=7.9, ,7=1.6, 8-H), 6.86-7.26 (m, 280 7H, Ar-H) , 4.17-4.45 (m, 5H, 2-H, 3-H, OCH2) , 2.42-2.64 (m, 2H, NCH2) , 2.26 (s, 3H, Ar-CH3) , 2.20 (s, 6H, N(CH3)2); TLC (hexane : acetone : TEA - 70 : 30 : 2) , Rf 0.47
Elemental analysis for fumaric acid salt C20H24 2O2 · C4H404
285 (440.50); m fumaric acid salt 97-104°C
C H N
calculated 65.44% 6.41% 6.36%
found 65.08% 6.25% 6.28%
EXAMPLE 2
Preparation of N,N-dimethyl-2- [ [3- (2-pyridinyl) -2, 3- dihydrochromen-4-ylidene] - amino] oxyethanamine
To a solution of 1- (2-hydroxyphenyl) -2-pyridin-2-yl-
290 ethanone (0.639 g, 0.003 mole) in DMF (12.0 mL) , N,N- dimethylformamide dimethyl acetal (0.465 g, 0.0039 mole) was added. The reaction mixture was stirred at room temperature for 6h. After completion, the reaction mixture was poured into water (100 mL) and extracted with
295 ethyl acetate . The organic layer was dried over anhydrous magnesium sulphate and concentrated to give the crude 3- (2-pyridinyl) -4H-chromen-4-one which was purified by column chromatography.
C14H9 O2 (223.23); yield 87 %; mp 117-118°C; H MR (CDCl3, 300 300 MHz , ppm) : δ 8.85 (s, 1H, 2-H), 8.60 (m, 1H, 6' -Hpy) ,
8.42 (d, J=8.1 Hz, 1H, 5-H) , 8.32 (d, J=8.1 Hz, 1H, 4'- Hpy) , 7.64-7.78 (m, 2H, 7-H and 8-H) , 7.40-7.51 (m, 2H, 6-H and 3' -Hpy) , 7.22-7.29 (m, 1H, 5' -Hpy) ; TLC (hexane : acetone - 75 : 25), Rf 0.57
305 3- (2-pyridinyl) -4H-chromen-4-one (0.23 g, 0.001 mole) in acetone (15 mL) , palladium on carbon (Pd/C 10 %, 0.1 g) was added. Subsequently, hydrogen atmosphere was applied, and after 4 h of stirring at room temperature, the next portion of Pd/C 10 %, (0.1 g) was added and the
310 resulting suspension was stirred for another 2 h. The progress of the reaction was monitored by TLC. The suspension was filtered, the filtrate was evaporated and the residue was purified by column chromatography.
C16Hi6N02 (225.25); yield 40 %; mp 119°C; XH MR (CDCl3,
315 300 MHz , ppm) : δ 8.56 (s, 1H, 6' -HPy) , 7.97 (dd, 1H,
«7=7.9, vJ=1.7, 5-H) , 7.69 (td, J=7.9 Hz, .7=1.7, 1H, 4'- Hpy) , 7.50-7.56 (m, 1H, 6-H), 7.44 (d, J=7.9, 1H, 7-H) , 7.24-7.28 (m, 1H, 8-H) , 7.00-7.11 (m, 2H, 3' -Hpy and 5' - Hpy), 5.34 (br s, 1H, 3-H), 4.81 (d, ,7=11.5, 1H, 2-H),
320 4.53 (d, »7=11.5, 1H, 2-H); TLC (hexane : acetone - 75 :
25), Rf 0.37
To a solution of 3- (2-pyridinyl) -2 , 3 -dihydro-4H-chromen- 4 -one (0.0097 g, 0.00043 mole) in mixture of pyridine (2.15 mL) and dry ethanol (0.86 mL) , 2- 325 (dimethylamino) ethoxyamine dihydrochloride (0.0015 g,
0.00086 mole) was added. The reaction mixture was stirred at 80 °C for 12 h while being monitored by TLC. After completion, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate. The organic 330 layer was dried over anhydrous magnesium sulphate. The solvent was evaporated to give the crude N,N-dimethyl-2- [ [3- (2-pyridinyl) -2, 3-dihydrochromen-4- ylidene] amino] oxyethanamine as a sticky oil which was purified by column chromatography.
335 C2oH24N202 (324.43); yield 88%; τΚ MR (CDC13, 300 MHz, ppm) : δ 8.51 (d, 1H, «7=4.8, 6' - Hpy) , 7.99 (d, 1H, .7=7.7, 8-H) , 7.67-7.77 (m, 2H, 4,-HPy and 7-H) , 7.26-7.34 (m, 1H, 6-H) , 7.12-7.16 (m, 1H, 5-H) , 6.98-7.03 (m, 2H, 3'- Hpy and 5' -HPy) , 4.05-4.18 (m, 4H, 2-H, OCH2) , 3.83-3.91
340 (m, 1H, 3-H), 2,73-2,83 (m, 1H, NCH2 isomer Z) , 2.22 (s,
6H, N(CH3)2), 1.99-2.05 (m, 1H, NCH2 isomer E) ; TLC (hexane : acetone : TEA - 70 : 30 : 2) , i?f 0.36
Elemental analysis for difumaric acid salt Ci8H2iN302 · 2C4H404 (543.54); mp difumaric acid salt=193 - 195 °C
C H N
calculated 57.46% 5.38% 7.73%
found 57.61% 5.18% 7.86%
345
All obtained final free bases were treated with methanolic fumaric acid and fumaric acid salts were precipitated with dry diethyl ether and crystallized twice from ethanol .
350 The compounds of this invention were established to be histamine. Hi-antagonists by subjecting them to the following standard test procedures for Hi-blocking activity:
Male guinea pigs weighing 300-400 g were sacrificed by a
355 blow on the head. The ileum was excised and placed in phosphate buffer at room temperature (pH 7.4) containing (mM) NaCl (136.9); KCl (2.68); NaHP04 (7.19). After flushing the intraluminal contens, segments of about 2 cm long were cut and mounted for isotonic contractions in
360 water jacked 20 mL organ baths filled with oxygenated
(02 : C02=95 : 5 , v/v) Krebs buffer containing (mM) NaCl (117.5); KCl (5.6); MgS04 (1.18); CaCl2 (2.5); NaH2P04 (1.28); NaHC03 (25); glucose (5.5) and indomethacin d-10"6 mol/L) at 37 °C under a constant load of 0.5 g.
365 After a 30 min equilibration period with washings every
10 mins, a sub maximal priming dose of histamine (1 μΜ) was given and washed out (standard washing procedure: 3 changes of buffer during 30 mins) . After washing out, the antagonistic activity of given compounds was measured by
370 recording a Concentration Response Curve (CRC) for histamine in the presence of the testing compounds which was added 10 mins before histamine. This procedure was repeated with higher concentrations of the compounds . The antagonism was of a competitive nature causing a parallel
375 shift of the CRC. The pA2-values were calculated according to O. Arunlakshana, H.O. Schild, Br. J. Pharmacol. 1959, 14, 48-58. The pA values were compared with the potency of pyrilamine.
Selected compounds were tested for H3 antagonistic
380 effects in vitro, following standard methods, using the guinea pig ileum (R.C. Vollinga, O.P. Zuiderveld, H. Scheerens, A. Bast, H. Timmerman, Meth. Find. Exp. Cli. Pharmacol. 1992, 105, 747-751). Male guinea pigs weighing 300-400 g were sacrificed by a blow on the head.
385 A portion of the small intestine, 20-50 cm proximal to the ileocaecal valve (jejunum) , was removed and placed in Krebs buffer (composition (mM) NaCl 118; KC1 5.6; MgS0 1.18; CaCl2 2.5; NaH2P04 1.28; NaHC03 25; glucose 5.5 and indomethacin (1 10"6 mol/L) ) . Whole jejunum segments (2
390 cm) were prepared and mounted between two platinum electrodes (4 mm apart) in 20 mL Krebs buffer, continuously gassed with 95% 02:5% C02 and maintained at 37 °C. Contractions were recorded isotonically under 1.0 g tension with Hugo Sachs Hebel- essvorsatz (Tl-2)/HF-
395 modem (Hugo Sachs Electronik, Hugstetten, Germany) connected to a pen recorder. After equilibration for one hour with washings every 10 min, the muscle segments were stimulated maximally between 15 and 20 Volt and continuously at a frequency of 0.1 Hz and a duration of 00 0.5 msec, with rectangular-wave electrical pulses, delivered by a Grass Stimulator S-88 (Grass Instruments Co., Quincy, USA). After 30 min of stimulation, five minutes before adding (R) -a-methylhistamine, pyrilamine (1·1(Γ5 mol/L concentration in organ bath) was added, and
405 then cumulative concentration-response curves (half-log increments) of (R) -a-methylhistamine, H3-agonist, were recorded until no further change in response was found. Five minutes before adding the tested compounds, the pyrilamine (1 10"5 mol/L concentration in organ bath) was
410 added, and after 20 minutes cumulative concentration- response curves (half -log increments) of (R) -a- methylhistamine, H3 -agonist, were recorded until no further change in response was found. Statistical analysis was carried out with the Students' t-test. In
415 all test p<0.05 was considered statistically significant.
The potency of an antagonist is expressed by its pA2 value, calculated from the Schild regression analysis where at least three concentrations were used. The pA2 values were compared with the potency of thioperamide . No
420 one shows any H3 -antagonistic activity (pA2<4; for thioperamide pA2=8.67) .
INDUSTRIAL APLICABILITY
The pharmacological results obtained characterize the compounds of this invention as Hi- receptor antagonists 425 useful in the treatment of mammals experiencing conditions such as asthma, hay fever, allergic rhinitis, atopic dermatitis, conjunctivitis, pruritis, and eczema, or other responses where histamine is released and acts on Hi receptors. As such, they may be administered 430 topically or systemically. Topical administration is advantageously achieved with creams, ointments or lotion, or via aerosol introduction into the respiratory tract. Systematic administration may be orally, nasally, intrabronchially, parenterally or rectally. In each 435 instance, conventional formulation amenable to use in desired administration route is appropriate. Hence, tablets and capsules may be prepared for oral administration, suppositories for rectal administration, isotonic aqueous solutions for intravenous, subcutaneous 440 of intramuscular injection and in aerosol suspensions for inhalation.
As is conventional in the use of anthistamine agents, the appropriate dosage is determined on a subjective basis for initial administration in small amounts, c.a. 0.5 -
445 15 mg, followed by increasing quantities up to about 400 mg. , depending upon the desired route of administration, until the desired symptomatic relief is obtained. The dosage is personalized in this manner for each patient, based upon size, age, type of discomfort, degree of
450 disability, etc., by the physician.

Claims

What is claimed is:
1 . A compound, including enantiomers, stereoisomers, cis-, trans-isomers and their racemic mixture and mixture of geometric isomers, or pharmaceutically acceptable salts or solvates of said compound, said compound having the general structure shown in formula (I)
wherein
R2 and R2 are, independently, hydrogen, halogen, Ci-3alkyl or Ci-3alkoxy;
R3 is phenyl optionally substituted by R4 and R5 which are, independently hydrogen, halogen, Ci-3alkyl, Cx. 3alkoxy, fluoro-, difluoro- and trifluoromethyl, nitrile group, N,N-diCi-3alkylamide, carboCi-3alkoxy or Ci- 3alkylsulphone groups; R3 is pyridynyl group containing nitrogen at various positions in the benzene ring, n is one of the integers 1 or 2 .
2 . The compound of claim ( 1 ) where Ri and R2 are Ci-
3alkyl groups, and R3 = phenyl, and the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine .
3. The compound of claim (1) where Ri and R2 are Ci_ 475 3alkoxy groups and R3 = phenyl, and the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine.
4. The compound of claim (1) where Ri and R2 are fluorine, chlorine or bromine groups and R3 = phenyl, and
480 the optional substituents in R4 and R5 are hydrogen, fluorine, chlorine or bromine.
5. The compound of claim (1) where Ri and R2 are hydrogen and R3 = phenyl, and the optional substituents in R4 are hydrogen or methyl or chlorine and R5 are
485 hydrogen or methyl or fluorine or chlorine or methyl group or methoxy group or nitrile group.
6. The compound of claim (1) where Rx and R2 are hydrogen, fluorine, chlorine or bromine and R3 unsubstituted pyridynyl, the pyridynyl moiety contains
490 nitrogen at 3 -position in benzene ring.
7. A pharmaceutical composition having histamine Hi- antagonists activity comprising a histamine blocking effective amount of a compound according to claim (1) and a pharmaceutically acceptable carrier.
495
EP13789395.4A 2013-09-30 2013-09-30 Novel substituted n, n-dimethylaminoalkyl ethers of isoflavanone oximes as h1-receptor antagonists Withdrawn EP3052482A1 (en)

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PL100895B1 (en) 1975-11-19 1978-11-30 METHOD OF THE PRODUCTION OF THE NEW OXYME ETHER CHLORIDE
JPS5829782A (en) * 1981-08-12 1983-02-22 Nippon Zoki Pharmaceut Co Ltd Novel heterocyclic compound, its preparation and medicinal composition containing said compound
US5210234A (en) * 1986-05-03 1993-05-11 Beecham Group P.L.C. Benzopyran intermediates
IL129999A (en) * 1996-12-10 2004-06-20 Bristol Myers Squibb Co Benzodioxole, benzofuran, dihydrobenzofuran, and benzodioxane melatonergic agents
DE19748469A1 (en) * 1997-11-03 1999-05-06 Hoechst Marion Roussel De Gmbh Sulfonamide-substituted benzopyran derivatives, processes for their preparation, their use as medicaments and pharmaceutical preparations containing them
ATE286893T1 (en) 2001-01-24 2005-01-15 Chiesi Farma Spa 2H-1-BENZOPYRAN DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND PHARMACEUTICAL COMPOSITIONS
US7259266B2 (en) * 2003-03-31 2007-08-21 Pharmacia Corporation Benzopyran compounds useful for treating inflammatory conditions
US7812183B2 (en) * 2005-09-01 2010-10-12 Janssen Pharmaceutica Nv Benzopyran derivatives as potassium channel openers

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